Schizophrenia, a particularly disabling psychiatric disorder, has been linked to early brain insult, altered neurodevelopment, and an intrinsic hypofunction of NMDA receptor neurotransmission. Researchers have proposed that treatment with antipsychotic drugs, initiated in the early stages of the disease, might slow or halt pathological brain changes in schizophrenia. We have developed a mouse model, the NMDA receptor hypomorphic (NR1-/-) mouse, for the intrinsic deficits in NMDA receptor function that may underlie symptoms in schizophrenia. This model has a behavioral phenotype that reflects alterations observed in the clinical disorder, including deficits in habituation and impaired sensorimotor gating in tests of prepulse inhibition. In addition, NR1-/- mice exhibit low levels of social preference and profound alterations in direct social interaction. Schizophrenia patients also exhibit deficits in social interaction and communication, sometimes well before the emergence of other signs of the disorder. Drugs used for treatment in schizophrenia are most effective against the overt, positive disease symptoms, and less efficacious against negative symptoms, including social withdrawal and anhedonia. The NR1-/- mouse provides a unique system for determining specific drug efficacy against recalcitrant negative symptoms and against disease progression, and for exploring neural mechanisms for behavioral deficits. The first goal of the following studies is to investigate the developmental time course for the emergence of aberrant behaviors, including impairments in social responses, sensorimotor gating, and habituation. The second goal of the proposal is to map the specific brain regions mediating the abnormal social responses characteristic of the NR1-/- mice. For this goal, measures of Fos and FosB immunoreactivity will be used to determine neuronal activation in specific regions in brain. A third goal is to evaluate whether chronic treatment with olanzapine or risperidone, initiated in the post- weanling period, will delay or prevent the deficits in social behavior, sensorimotor gating, and habituation observed in the hypomorphic mice. Results will be compared with chronic haloperidol treatment, to determine if the atypical drugs have differential efficacy against changes in the NR1 hypomorphic mice. For the final goal, Fos and FosB expression will be used to determine the effects of early intervention with antipsychotics on aberrant neuronal activity across multiple regions in brain. Overall, these studies will elucidate the neurodevelopment effects of intrinsic NMDA receptor hypofunction on behavior and regional brain activity, as possible underlying mechanisms and potential targets for therapeutic intervention in schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a severe neuropsychiatric syndrome, usually first diagnosed in late adolescence or early adulthood. We have developed a genetic mouse model, the NR1 hypomorphic mouse, for deficient glutamate function relevant to schizophrenia. This proposal would determine the time course in development for the onset of abnormal behavior in the mouse model, and examine whether treatment with antipsychotic drugs, initiated in adolescence, could have beneficial effects on behavior and brain activity in the NR1 hypomorphic mice.